The most important stimulant neurotransmitter of the central nervous system consists of glutamic acid. The neurotransmitter receptors of glutamic acid can be divided into two groups: ionotropic receptors (i.e. receptors connected with an ionic channel) and metabotropic receptors. The ionotropic receptors take part in nearly each process of the central nervous system, for example in the processes of learning, in any type of memory, in processes accompanied by acute and chronic neuro-degeneration (or cellular destruction). The ionotropic receptors have role in pain sense, motoric function, urination reflex and cardiovascular homeostasis, too.
Two types of ionotropic stimulant receptors exist: the NMDA and the AMPA/kainate receptors. The receptors of AMPA/kainate type are, primarily, responsible for the so called fast synaptic processes, while the NMDA receptors regulate the slow synaptic processes prepared by the fast synaptic ones. Thus, antagonists of the AMPA/kainate receptors may have an indirect influence on the function of the NMDA receptors. Consequently, several processes of the central nervous system and the whole organism can be regulated by the antagonists of the AMPA/kainate receptors.
Two types of AMPA/kainate receptor antagonists exist: competitive and non-competitive antagonists. Because of the different character of inhibition, non-competitive antagonists are preferred to the competitive antagonists. The first representative of the non-competitive antagonists was 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine synthetized about 15 years ago. Since the discovery of this compound numerous 2,3-benzodiazepines having non-competitive AMPA/kainate effect have been prepared [Donevan, S. D. et al., J. Pharmacol. Exp. Ther., 271, 25–29 (1994); Vizi, E. S. et al., CNS Drug Reviews, 2, 91–126 (1996)].
The therapeutical use of 2,3-benzodiazepines having non-competitive antagonist effect on the AMPA/kainate receptor is extremely various. They can be employed as a neuroprotective agent in case of different acute and chronic symptoms accompanied by neurodegeneration (Parkinson's disease, Alzheimer's disease, stroke etc.), furthermore for the improvement of many symptoms e.g. in epilepsy, spasmolysis, relief of pain, influencing emesis, schizophrenia, migraine and also as an anxiolytic agent [Tarnawa, I. and Vizi, E. S., Restorative Neurol. Neurosci., 13, 41–57 (1998)].
The Hungarian Patent Application No. P 97 00688 and the corresponding GB-P No. 2 311 779 described, among others, 1-(4-aminophenyl)-3-alkanoyl-4-methyl-3H-2,3-benzodiazepine derivatives that might have contained also a chloro atom in position 7 and/or 8. The known compounds have antispasmodic, muscle relaxant and neuroprotective activity and can be used for the treatment of neurological and psychiatric disorders.
The scope of compounds claimed in the above patent includes 2,3-benzodiazepines wherein the phenyl group being in position 1 contains, in addition to the amino group in position 4, also a halo atom or a C1-4 alkyl group in position 3. However, such compounds have not been examplified, and neither the identification data, nor the biological effect thereof have been described.
In our animal experiments it was found that during the metabolism that took place in the animal organism after the administration of the above known compounds, at first, the amino group being in position 4 at the phenyl group in position 1 was acetylated. (Further on, in the description, it is called N-acetylation). Due to N-acetylation, the therapeutical effect of the compounds is reduced. Since human beings can be of fast or slow acetylator phenotype, it is difficult to determine the proper therapeutical dose in the treatment. Therefore, the aim of the invention is to find 2,3-benzodiazepine derivatives characterized by decreased rate of acetylation since in this case human beings of fast and slow acetylator phenotype, respectively, can be treated with essentially the same dose of active ingredient.